Second Genetic Link To Weight And Obesity - New DNA Variants Found That Can Help To Pile On The Pounds

A study of 90, 000 people has uncovered new genetic variants that influence fat mass, weight and risk of obesity. The variants act in addition to the recently described variants of FTO gene: adults carrying variants in both genes are, on average, 3. 8 kg ( or 8. 5 lb ) heavier.

The variants map close to a gene called MC4R: mutations in this gene are most common genetic cause of severe familial obesity. The study highlights power of large collections of volunteer samples to uncover common variants that influence health.

" By working together with many international groups we've been able to assemble a sample collection which was large enough to allow this finding to be made, " explains Dr Ruth Loos, leading author from Medical Research Council Epidemiology Unit. " Several groups had shown that rare, highly disruptive variants in MC4R gene were responsible for very severe, genetic forms of obesity: this collaboration has uncovered more common variants that affect more people. "

The study, published in Nature Genetics , is led by investigators from Cambridge GEM consortium ( Genetics of Energy Metabolism ) and Oxford University and is a collaboration between 77 institutions from UK, USA, France, Germany, Italy, Finland and Sweden.

The team studied more than 77, 000 adults and found that two copies of genetic variants resulted in an average increase in weight of about 1. 5 kg.

This is second set of common variants that are associated with weight and obesity, following the study, involving many of same team, published in April 2007 that uncovered a role for FTO gene. People who carry two copies of an FTO variant are about 2 - 3 kg heavier than those who have no copies of variant.

Importantly, effects of the new gene add to those of FTO; people who carried both FTO variant and new variants were on average 3. 8 kg ( 8. 5 lb ) heavier.

" This is a great example of how cooperation can bring about new findings that can be missed when researchers work in isolation, " explains Dr Inês Barroso, Investigator at Wellcome Trust Sanger Institute and one of senior authors on the study. " The precise role in obesity of genetic variants in FTO and near MC4R remains to be discovered, but we can now begin to understand biological consequences of these variants. This is where this research will make a difference. "

MC4R protein plays a pivotal role in many aspects of physiology, including regulation of appetite and energy expenditure. The severe form of MC4R-related obesity is a consequence of alterations in gene sequence, resulting in an inactive or less active MC4R protein.

By contrast, the new variants lie some distance from the MC4R gene. The team suspect that the sequence variant changes activity of the MC4R gene, perhaps by disrupting DNA regions required for normal activity of MC4R.

" Through this new and powerful genetic approach we're increasingly finding that the genes known to play a role in severe - but rare - diseases are also implicated in much more common disease, " explains Professor Mark McCarthy, Robert Turner Professor of Diabetes at University of Oxford, UK. " The common variants we're uncovering don't have such a dramatic effect on normal functioning of gene as do the rare mutations in MC4R that can cause rare examples of very serious, early onset obesity. "

Dramatically, in a study of almost 6000 children, they found that effects were almost double those seen in adults. Between ages of four and seven, this additional increase in weight was result, almost exclusively, of gain of fat tissue, and not due to gain in muscle or other solid tissues.

This more dramatic effect in young children reflects more extreme consequences seen with rare variants of MC4R that severely disrupt its activity, suggesting that novel variants do indeed exert their effect through action on MC4R.

" Our work to understand common disease, such as obesity, depends on the participation of thousands of people - members of the public who provide samples, " explains Professor Nick Wareham, Director of MRC Epidemiology Unit. " Without their willing participation, we could never achieve power in our research to make striking findings like this.

" For each discovery, our efforts and the contribution of participants will lead to improved healthcare for population at large. "

The team will now look to uncover how DNA variants affect activity of MC4R protein, which is a key player in orchestrating information from body to control appetite and energy expenditure to keep body weight in balance. The team propose that altered activity of MC4R, imposed by variants, might reduce its ability to carry out this important role.

The team emphasize that, although gene variants can affect weight, body mass index and obesity, they're only part of story: lifestyle actions such as good diet and regular exercise are vital to control of weight.

Publications details

'Association studies involving over 90, 000 people demonstrate that common variants near to MC4R influence fat mass, weight and risk of obesity. ' Loos RJF et al. ( 2008 ) Nature Genetics Published online on Sunday 4 May 2008 doi: http: //dx. doi. org/10. 1038/ng. 140

Participating groups

A full list of participating groups can be found at Nature website.

The Cambridge Genetics of Energy Metabolism ( GEM ) consortium includes researchers from the Wellcome Trust Sanger Institute, MRC Epidemiology Unit and University of Cambridge Department of Clinical Biochemistry and brings together teams with diverse skills to tackle task of understanding genetics of both common polygenic forms and also rare monogenic forms of diabetes and obesity.

Funding

This research programme was supported by Medical Research Council, Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, European Commission, Academy of Finland, British Heart Foundation, National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline, and German National Genome Research Net.

Additional support was provided to individuals by US National Institute of Diabetes and Digestive and Kidney Diseases, Throne-Holst Foundation, Vandervell Foundation, American Diabetes Association, Unilever Corporate Research and British Heart foundation.

The Wellcome Trust Sanger Institute, which receives majority of its funding from Wellcome Trust, was founded in 1992 as the focus for UK sequencing efforts. The Institute is responsible for the completion of sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by Wellcome Trust to enable Institute to build on its world-class scientific achievements and exploit wealth of genome data now available to answer important questions about health and disease. These programmes are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, UK.

http: //www. sanger. ac. uk

Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe and Oxford is ranked third in world for biomedicine. The Medical Sciences Division represents almost one third of Oxford University's income and expenditure and two thirds of Oxford University's external research income. Work ranges from basic science including leading molecular research to studies in humans, with vaccines in field trials for HIV, TB and malaria.

http: //www. ox. ac. uk

The Medical Research Council supports best scientific research to improve human health. Its work ranges from molecular level science to public health medicine and has led to pioneering discoveries in our understanding of human body and the diseases which affect us all.

http: //www. mrc. ac. uk/

GlaxoSmithKline - one of world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information, visit GlaxoSmithKline at http: //www. gsk. com.

GlaxoSmithKline sponsored, in part, the CoLaus Study in Lausanne, Switzerland. This study is one of a large panel of academic-industry collaborations that GlaxoSmithKline has set up to decipher genetic basis of common diseases. Scientists from GlaxoSmithKline and from Lausanne University Hospital collaborated closely with MRC and Sanger scientists and were involved in collection and analysis of the data which led to the present publication.

The Wellcome Trust is largest charity in UK. It funds innovative biomedical research, in UK and internationally, spending around £650 million each year to support the brightest scientists with best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. http: //www. wellcome. ac. uk

Wellcome Trust Sanger Institute

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